Cannabinoid research has made tremendous advances since the discovery of specific recognition sites (receptors) for chemicals like ? -9-THC, the main active ingredient in marijuana. The endocannabinoid signaling system thus likely serves as the biological substrate for the marijuana "high". This subjective state presumably underlies human marijuana consumption that may lead to compulsive cannabis intake and dependence disorders. Drug discrimination (DD) is a powerful model for assessing "subjectively" experienced drug effects in animals and is the major in vivo behavioral technique in this proposal. Both cannabinoid receptor CB1 (CB1R) agonists and antagonists (inverse agonists) will be trained in DD using different doses. This provides for in vivo assays with different sensitivity levels. This research is complemented by observational studies as well as schedule controlled responding allowing for a detailed characterization of the ligands. A major goal of this proposal is to identify new medications that will translate into better pharmacotherapies for combatting escalating marijuana addiction. New molecules are designed and synthesized by on site expertise. A particular focus is to identify in vivo neutral CB1R antagonists. Currently available CB1R antagonists (such as rimonabant) also exhibit intrinsic activity (inverse agonism) that may interfere with patient compliance in treatment settings. Thus, the studies will expand our understanding of the endocannabinoid signaling system, comprising two major family members as represented by anandamide and 2-arachidonoylglycerol (endogenous receptor ligands) acting on two known receptors, CB1 and CB2, in normal body function as well as under pathological conditions. Additional "therapeutic" targets for this proposal concern ligands affecting enzymes involved in the deactivation of the endocannabinoids and a less well characterized membrane transport system, thus potentially avoiding direct receptor activation. The behavioral studies are aided by neuro/biochemical techniques provided by collaborating faculty in pursuing these goals. By obtaining information on the functions of the body substances (anandamide and 2-AG) and the marijuana substance ?-9-THC, as well as possible in vivo neutral blocking agents, these studies will not only add to our understanding of the behavioral neurobiology of cannabis abuse and dependence, but may also lead to the development of effective medications for treating cannabis / marijuana disorders.